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Introduction
Cardiovascular disease (CVD) stands as the foremost cause of death and illness globally [1]. In 2020, it was responsible for over 10 million fatalities worldwide [2]. Research has shown that hypertension and dyslipidemia play critical roles in the development of CVD [3], with a substantial number of individuals with high blood pressure (BP) also exhibiting dyslipidemia [1,2,4]. The combined presence of hypertension and dyslipidemia significantly increases the risk of coronary heart disease beyond the additive risks of each condition alone [5]. Given the interconnected nature of cardiovascular risk factors such as elevated BP and abnormal lipid levels, it is essential to address both conditions to minimize the risk of future cardiovascular incidents [6,7].
Endothelial dysfunction is a crucial early factor in the onset of atherosclerosis and is considered a major predictor of CVD risk [8]. In terms of cardiometabolic parameters, epicardial adipose tissue plays a significant role in endocrine and inflammatory processes [9]. Its proximity to the atrial myocardium indicates it may contribute to the development of cardiac diseases related to metabolic disorders [9]. Epicardial adipose tissue has also been implicated in insulin resistance and promotes a pro-inflammatory milieu, further linking its pathophysiological role to metabolic disorders such as type 2 diabetes and coronary artery disease [10].
Managing hypertension and dyslipidemia has primarily involved aerobic exercise and medication. Aerobic exercise has consistently been effective in lowering the incidence and mortality rates associated with cardiovascular complications. Recently, a novel approach to physical activity has emerged with advanced gaming technology, known as exergaming or active video gaming. Exergames are video games that necessitate physical activity as part of gameplay [11]. This form of exercise is gaining traction in both the entertainment sector and rehabilitation settings [12], showing promise in enhancing physical activity levels and cardiovascular fitness [12,13], particularly among older adults [14].
However, medication will be needed if normal BP and lipidemia cannot be achieved through exercise and lifestyle changes. Rosuvastatin/olmesartan showed good efficacy and safety profiles in patients with both hypertension and dyslipidemia [15,16]. Nevertheless, no studies so far have examined the actions of rosuvastatin/olmesartan in combination with aerobic exercise on endothelial function and epicardial adipose tissue in patients with hypertension and dyslipidemia.
In this study, we sought to (1) evaluate the effects of olmesartan/rosuvastatin alone or in combination with aerobic exercise programs on endothelial function and epicardial fat thickness (EFT) and (2) compare the effects of exercise programs on endothelial function and EFT in patients with hypertension and dyslipidemia.
Methods
Ethical statements: This study was approved by the Institutional Review Board of Kosin University Gospel Hospital (IRB No. 2016-06-029). Written informed consent was obtained from the patients to participate in the study.
1. Study design and population
This single-center study was conducted from February 2017 to August 2017. Ninety-nine patients with hypertension and dyslipidemia who had been sedentary and had not engaged in any type of regular exercise training for at least 3 months prior to this study were enrolled. If patients were taking medications, they were required to undergo a wash-out period of at least 2 weeks for antihypertensive medications and 4 weeks for statins before participating in this study. Patients who were pregnant; current smokers; alcohol users; and those with uncontrolled hypertension, renal failure, established CVD, chronic obstructive pulmonary disease, or musculoskeletal disease were excluded.
The subjects were randomly assigned to the treadmill or exergame or control group. This study period lasted 6 months, during which the first 3 months were dedicated to evaluating the effects of medication alone, while from months 3 to 6, the combined effects of medication and exercise were assessed (Fig. 1). Subjects attended a total of three visits for measurements. At each visit, venous blood was drawn to measure glucose and lipids profiles after an 8-hour overnight fast, and BP, height, and weight were recorded. Additionally, flow-mediated dilation (FMD) and EFT were measured. In premenopausal women, blood sampling was performed at the follicular phase of the menstrual cycle.
The numbers and reasons for early withdrawal from the study are presented in Fig. 1. During the medication treatment period, six participants were unable to complete the training program: five for tracking fail and one for withdraw consent (scheduling difficult). During the medication and exercise treatment period, 18 participants were unable to complete the training program: six for tracking failed, 12 for withdraw consent (seven owing to insufficient attendance, three for scheduling difficult, two for fatigue one for personal reasons). Thus, a total of 75 participants were included in our data analysis.
2. Measurement FMD and EFT
FMD was assessed in the brachial artery following established guidelines. A two-dimensional ultrasound system (Vivid 7; General Electric) equipped with a 10-MHz linear-array transducer was used for the measurements. After obtaining baseline readings, reactive hyperemia was triggered by inflating a pneumatic cuff on the forearm to 180 to 200 mmHg, which is 50 mmHg above the systolic BP, and maintaining this pressure for 5 minutes. The brachial artery’s peak diameter was recorded 40 to 60 seconds after the cuff was rapidly deflated. The percentage change in FMD due to reactive hyperemia was calculated relative to the baseline diameter (%FMD=100×[diameter post-hyperemia–baseline diameter]/baseline diameter). Each diameter was measured three times during two heartbeats at the peak of the R wave on the surface electrocardiogram, with the average value used for the final analysis.
The echocardiographic measurement of EFT was defined as the echo-free region between the myocardium's outer wall and the visceral pericardium [15]. Standard echocardiography was performed with the participant in the left lateral decubitus position using a 3.5 MHz transducer (Philips iE33; Philips Medical Systems). The EFT was measured vertically from the free wall of the right ventricle at the end-systolic phase over three cardiac cycles. The recorded EFT value was determined by averaging measurements from the parasternal long-axis view, the parasternal short-axis view at the level of the papillary muscles, and the apical four-chamber view at the right ventricular free wall to ensure consistent evaluation. To reduce observational bias during both initial and follow-up analyses, the researcher conducting the measurement was blinded to the baseline values. A reliability analysis using intra-class correlation coefficient was performed to obtain the intra-observer variability. The intra-observer variability of the EFT was 3.2%.
3. Exercise program
Exercise training was carried out at the Kosin University Convergence Medicine & Exercise Science Research Institute under the close supervision of a qualified director. Both the exergame and treadmill groups followed an exercise regimen that included a 5-minute warm-up, a 40-minute main session, and a 5-minute cool-down. Participants who completed less than 80% of the 12-week exercise program were excluded from the study. The control group was instructed to maintain their usual level of physical activity over the 12-week period.
For the treadmill group, the exercise involved 40 minutes of walking or jogging at an intensity of 60% to 80% of the heart rate (HR) reserve. Exercise intensity was calculated using the Karvonen formula: target HR=(exercise intensity×[HR max–resting HR])+resting HR. HR was monitored during each session using a HR monitor (Polar RS400sd, Pola).
The exergame group exercised with the Exerheart device (D&J Humancare), which included a running/jumping platform connected to a screen (Fig. 2A). The exercise sessions involved playing the exergame “Alchemist's Treasure,” where the player's movements on the platform controlled an avatar in the game. The game required the user to run with the avatar, avoid obstacles, and collect items by utilizing sensors on the front, back, left, and right of the exercise platform (Fig. 2B).
One of the primary benefits of exergaming is the enjoyment it provides. In this study, exercise intensity was not strictly controlled to enhance participants' enjoyment of the exergame. Thus, during the training period, the population exercised at a self-selected pace for 40 minutes per day. Individual exercise intensity was monitored using a HR monitor (Polar RS400s), and data on resting, minimum, maximum, and average HRs were collected throughout the exergame sessions. The participants' resting HR averaged 79±12 beats per minute (bpm), with a minimum of 98±26 bpm, a maximum of 153±28 bpm, and a mean HR of 120±19 bpm. Based on American College of Sports Medicine guidelines [17], the exercise intensity for exergaming typically falls within 42% to 82% of HR reserve.
4. Statistical analysis
Baseline characteristics across the groups were assessed using a one-way analysis of variance (ANOVA) for continuous variables. To compare variables both between and within groups, a two-way ANOVA (group×time) with repeated measures was employed. Bonferroni post hoc tests were conducted to determine the significance of any findings identified by the one-way or two-way ANOVA. All values are expressed as mean±standard deviation, and statistical significance was defined as p<0.05. Statistical analyses were performed using IBM SPSS ver. 21.0 (IBM Corp.).
Results
1. Baseline characteristics of study participants
Ninety-nine patients enrolled for the study and run-in drug therapy. Among these, 93 patients were randomized to one of the treatment groups (31 to the treadmill group, 31 to exergame group, and 31 to the control group), and 75 completed the study (22 in the treadmill group, 29 in the exergame group, 24 in the control group). The numbers and reasons for early withdrawal from the study are presented in Fig. 1. Patient demographics and baseline characteristics showed no differences between the three groups (Table 1). The mean patient age was 61.3 years, and 26.7% were male.
2. Primary outcomes
FMD levels significantly improved in both the treadmill and exergame groups between weeks 12 and 24 (both p<0.01). However, no changes in FMD were observed at week 12 compared to baseline levels. Compared to the control group, significant improvements in FMD were noted in the treadmill and exergame groups from week 12 to week 24 (both p<0.05). There were no significant differences in FMD between the treadmill and exergame groups (Fig. 3A).
The EFT levels were significantly decreased in treadmill and exergame groups from week 12 to week 24 (both p<0.01). However, at week 12, there were no changes in EFT compared with baseline levels. Compared with the control group, a significant improvement in EFT was observed for treadmill and exergame groups from week 12 to week 24 (both p<0.05). There were no differences between treadmill and exergame groups (Fig. 3B).
3. Other clinical outcomes
At week 12, systolic BP, diastolic BP, total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, fasting blood glucose (FBG), and glycosylated hemoglobin (HbA1c) levels were significantly decreased compared with baseline (both p<0.01). At week 12, alanine aminotransferase levels were significantly increased compared with baseline (p<0.05). Systolic BP and diastolic BP had additionally decreased only in the treadmill group from week 12 to week 24 (both p<0.05, with no group differences). However, there were no additional changes in total cholesterol, LDL-C, triglycerides, FBG, and HbA1c levels in any of groups from week 12 to week 24 (Tables 2,3).
Discussion
In this study, while the reduction in BP, lipid profiles, and glucose levels was primarily due to the effects of medication, we found that exercise had a greater impact on improving endothelial function and decreasing EFT in patients with hypertension and dyslipidemia. This study was designed to evaluate the effects of treadmill exercise and exergaming on these parameters. The results showed that both exercise programs significantly improved FMD and EFT, while systolic BP decreased only in the treadmill group, supporting previous findings that exercise positively impacts cardiovascular health.
The effects of angiotensin Ⅱ receptor blocker (ARB)/statin combination on lipid profiles and BP reduction have been verified. The study by Naya et al. [18] provides evidence that treatment with an ARB (olmesartan medoxomil) has a beneficial effect on the coronary microcirculation and improves endothelium-dependent coronary dilation independent of lowering BP. In addition, statin therapy significantly improved endothelial function, as assessed by FMD [19] and reduced epicardial fat [20]. However, the effects of these drugs on endothelial function and epicardial fat remain unclear. We found that medical therapy with these drugs did not significantly reduce FMD and EFT, but a significant reduction was observed when the drugs were combined with exercise.
The effectiveness of conventional exercise in enhancing endothelial function among patients with cardiovascular or chronic diseases is well-established [21]. However, there is limited research on how exergaming impacts endothelial function. In this study, both the treadmill and exergame groups demonstrated significant improvements in FMD, with no notable differences between them. This finding implies that exergaming can offer similar benefits to traditional aerobic exercise in terms of improving endothelial function. Exercise is known to lower BP through various mechanisms, with enhanced endothelial function playing a crucial role in its antihypertensive effects [22]. Nonetheless, only the treadmill group exhibited further reductions in BP, with no significant changes observed in other clinical measures. This suggests that treadmill exercise may be more effective for long-term management of BP.
Recent studies have indicated that EFT may serve as a better indicator of visceral fat and a more significant cardiometabolic risk factor than overall fat accumulation disorders [23]. While physical exercise is widely recognized as the primary intervention for metabolic syndrome associated with increased adipose tissue [24], there is still limited research on how exercise impacts EFT. In this study, although there was no significant difference compared to the control group, both the treadmill and exergame groups demonstrated reductions in EFT by 11.8% and 18.4%, respectively. Previous research has reported that exercise can reduce EFT in postmenopausal women with metabolic syndrome [25] and in obese individuals [26]. However, other studies have found no significant reduction in EFT among patients with type 2 diabetes mellitus following 6 months of exercise training [27].
Several mechanisms have been suggested to explain the reduction in visceral adipose tissue, including the release of hormones that promote fat breakdown [28], increased energy expenditure following exercise [29], and enhanced fat oxidation that contributes to a more substantial negative energy balance [30]. Although the mechanisms involved in epicardial adipose tissue are not well-known, epicardial adipose tissue is an indicator of visceral adipose tissue [31]. Therefore, it can be inferred that the same mechanisms led to the reduction in EFT in the treadmill and exergame groups in this study.
Exergaming showed higher exercise adherence compared to the treadmill group. The drop-out rate was 13.9% in the treadmill group, while it was 4.5% in the exergame group. Although this study did not measure enjoyment directly, it is believed that exergaming offered greater enjoyment and motivation than treadmill exercise. Research suggests that exergaming can produce higher levels of enjoyment compared to traditional exercise activities. Enjoyment in an activity can enhance attendance and adherence, leading to increased physical activity and improved health benefits. This suggests that exergaming may be a more enjoyable and engaging form of exercise. Additionally, new exercise forms like exergaming can provide health benefits similar to those of traditional aerobic exercise.
Although no statistical difference was observed for high sensitivity C-reactive protein (HS-CRP), the improvement in HS-CRP appears slightly more pronounced in the control group that received only drug treatment compared to the exercise groups. However, it is considered to have minimal or no clinical impact on patient care. We believe it is not clinically significant and does not affect the interpretation of the main findings. Further research may be required to confirm whether this difference has any clinical relevance.
We acknowledge several limitations in our study that may have impacted our outcomes. First, measurement of EFT using ultrasound. While ultrasound is a widely used method for assessing EFT, it may be subject to operator dependency and variability in measurements. Second, our study only evaluated the “Alchemist's Treasure” game with the Exerheart, so the results cannot be generalized to all exergame exercise programs. Third, we observed low adherence and high drop-out rates in both the treadmill and control groups. This reflects real-world challenges, as patients with no prior exercise experience may struggle to maintain traditional aerobic treadmill exercises. Finally, our findings highlight the importance of enjoyment and motivation in exercise. Future research should focus on the enjoyment levels of different exercise types, generalizing findings across various exergame programs, incorporating direct measurements of cardiorespiratory fitness, and examining the impact of exercise enjoyment on adherence and health outcomes. By addressing these areas, we can gain a better understanding of the potential benefits of innovative exercise forms, such as exergaming, in improving cardiovascular health and managing chronic diseases.
This study demonstrates that both treadmill exercise and exergaming significantly improve endothelial function and reduce EFT in patients with hypertension and dyslipidemia. While the reduction in BP, lipid profiles, and glucose levels was primarily attributed to medication, exercise was shown to have a greater impact on enhancing cardiovascular health markers, such as FMD and EFT. These findings support the notion that exercise, whether traditional or exergame-based, plays a crucial role in cardiovascular health management. Notably, exergaming both produced similar improvements in endothelial function and epicardial fat reduction as traditional treadmill exercise and exhibited higher exercise adherence and lower drop-out rates. This suggests that exergaming may be a more engaging and sustainable form of exercise for patients, potentially leading to better long-term health outcomes.
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